JP7366545B2 - Composition for improving appetite - Google Patents

Description

Application of Article 30, Paragraph 2 of the Patent Act January 10, 2018 Published as a dissertation (master's course) at Jichi Medical University

The present invention relates to a composition for improving anorexia containing a TRPA1 agonist, and particularly to a composition for improving anorexia in elderly people, anorexia in ghrelin-resistant subjects, and/or stress-induced anorexia.

Transient receptor potential ankyrin 1 (TRPA1) is a type of non-selective cation channel that belongs to the superfamily of transient receptor potential (TRP) ion channels. TRPA1 is mainly expressed in large amounts in somatic sensory nerves (spinal sensory nerves and trigeminal nerves), and functions as a nociceptor involved in pain, spiciness, and the like. In addition, TRPA1 is expressed in large quantities in the afferent vagus nerve, which is involved in feeding regulation, in addition to the somatosensory nerve.

Various compounds or plant extracts are known as agonists that activate TRPA1 (Patent Documents 1 to 9). In particular, the spiciness components of spices or spicy vegetables include those that act as TRPA1 agonists, and such TRPA1 agonists transmit peripheral information to the brain via sensory nerves including the afferent vagus nerve. It is known to increase food intake in healthy mice (Non-Patent Document 1). On the other hand, it is known that ghrelin, a peptide hormone produced in the stomach, cannot improve age-related loss of appetite, although it has an effect of increasing food intake (Non-Patent Document 2).

Japanese Patent Application Publication No. 2018-177739 Special table 2017-518963 publication JP2017-096785A Japanese Patent Application Publication No. 2014-210725 Japanese Patent Application Publication No. 2014-169240 Japanese Patent Application Publication No. 2014-076979 JP2014-024810A Special Publication No. 2011-506289 International Publication No. 2009/123080

Mishima Kaiun Memorial Foundation Research Report (2014), Volume 51, pp. 53-56 Endocrinology (2010), Vol. 151, pp. 244-252

As mentioned above, even if a component has an effect of increasing food intake in healthy subjects, it does not necessarily have an effect of improving anorexia, so TRPA1 agonists can improve specific anorexia conditions. Whether that is the case remains unclear. Therefore, the present invention aims to apply a TRPA1 agonist to specifically improve anorexia.

As a result of intensive studies to solve the above problems, the present inventors discovered that TRPA1 agonists can improve anorexia in elderly people who are resistant to ghrelin, and that TRPA1 agonists can improve stress-induced anorexia. The present invention has been completed. That is, the present invention provides the following composition for improving anorexia.
[1] A composition for improving anorexia in elderly people, comprising a transient receptor potential ankyrin 1 (TRPA1) agonist.
[2] The composition according to [1] above, wherein the elderly person is ghrelin resistant.
[3] A composition for improving anorexia in a ghrelin-resistant subject, comprising a TRPA1 agonist.
[4] A composition for improving stress-induced anorexia, containing a TRPA1 agonist.
[5] Any one of [1] to [4] above, wherein the TRPA1 agonist is at least one selected from the group consisting of diallyl trisulfide, allicin, allyl isothiocyanate, cinnamaldehyde, myogadial, and myogadial. The composition described in.

According to the present invention, a TRPA1 agonist can improve anorexia in elderly people, anorexia in ghrelin-resistant subjects, and/or stress-induced anorexia. Therefore, it is possible to provide a composition containing a TRPA1 agonist for improving these specific anorexia.

Cumulative food intake of young mice with and without ghrelin administration is shown. Cumulative food intake of young mice with and without DATS administration is shown. Cumulative food intake of aged mice with or without ghrelin administration is shown. Cumulative food intake of aged mice with or without DATS administration is shown. The cumulative food intake of mice with stress-induced anorexia with or without DATS administration is shown. (Different symbols a to c mean that there is a significant difference between the groups to which they are attached.)

The present invention will be explained in more detail below.
The composition for improving anorexia in elderly people, the composition for improving anorexia in ghrelin-resistant subjects, or the composition for improving stress-induced anorexia of the present invention is characterized by containing a TRPA1 agonist.

The term "TRPA1 agonist" as used herein refers to a substance that can act agonistically on the receptor TRPA1 to activate it. The activation effect of TRPA1 by the TRPA1 agonist can be detected, for example, by measuring the intracellular Ca ²⁺ concentration of isolated afferent vagus nerve cells, and as an effect of increasing this concentration. As the TRPA1 agonist, any substance commonly used in the art can be used without particular limitation, but for example, the TRPA1 agonist may be a component contained in spices or spicy vegetables. Preferably, it is at least one selected from the group consisting of diallyl trisulfide (DATS), allicin, allyl isothiocyanate (AITC), cinnamaldehyde, miogadial, and miogatrial. Further, the TRPA1 agonist may be a compound or a plant extract described in the claims and examples of Patent Documents 1 to 9 mentioned above, respectively.

The amount of the TRPA1 agonist in the various anorexia-improving compositions of the present invention is not particularly limited as long as the anorexia-improving effect is achieved. Furthermore, the dosage of the TRPA1 agonist is not particularly limited as long as it has an anorexia-improving effect, and may be adjusted as appropriate depending on the administration route, the subject's weight, sex, age, or other conditions. For example, when DATS is orally administered to humans, the daily dose per adult may be about 50 to about 2000 mg, preferably about 500 to 1000 mg.

In one aspect, the composition for improving anorexia of the present invention can improve anorexia in the elderly (anorexia associated with aging). It is thought that one of the reasons why anorexia is induced with aging is that the action of ghrelin is weakened and the elderly become ghrelin resistant. That is, the composition for improving anorexia of the present invention can also improve anorexia in ghrelin-resistant subjects. Although not bound by any particular theory, the following mechanism of action is considered for the composition for improving anorexia of the present invention. First, the brain action from the afferent vagus nerve is essential for the action of ghrelin to increase food intake. In a ghrelin-resistant state where receptor signaling of ghrelin receptors (metabotropic receptors) is abnormal, it is thought that ghrelin has difficulty acting on the afferent vagus nerve, leading to anorexia. It will be done. On the other hand, TRPA1 agonists such as DATS can bind to the ligand-gated cation channel TRPA1, open the TRPA1 channel, and strongly depolarize the nerves that express it. Therefore, TRPA1 agonists such as DATS, which can activate the afferent vagal subclass of the hyperphagic system through a pathway different from ghrelin receptor signaling, are thought to be able to improve anorexia in ghrelin-resistant subjects.

In another aspect, the composition for improving anorexia of the present invention can improve stress-induced anorexia. In other words, even in subjects with stress-induced anorexia, activating the afferent vagal subclass of the feeding hyperphagia system by depolarizing the nerves that express TRPA1 is thought to be effective in improving stress-induced anorexia. It will be done.

In elderly subjects, subjects with ghrelin resistance, or subjects with stress-induced anorexia, to whom the composition for improving anorexia of the present invention is applied, TRPA1 is expressed in the afferent vagus nerve of the hyperphagic system. Although not particularly limited, it may be a mammal, preferably a human.

Various compositions for improving anorexia of the present invention may further contain additional active ingredients or may be used in combination with additional active ingredients, as long as they do not interfere with the activity of the TRPA1 agonist. The additional active ingredients are not particularly limited, but include, for example, itopride hydrochloride, domperidone, metoclopramide, Rikkunshito, Hankashashinto, Hankashashinto, Juzentaihoto, Ninjinyoeito, and Heiji. It may also be an anorexia improving agent or an eating enhancer such as gastrosan.

Various compositions for improving anorexia of the present invention can be used, but are not particularly limited to, pharmaceuticals, quasi-drugs, supplements, or foods (general foods, foods for specific uses such as foods for patients, foods for specified health uses, nutritional It may also be a functional food, a food with health claims such as a food with functional claims), or a material for blending into these. The composition may further contain any pharmaceutically or food-acceptable excipients or additives and/or food raw materials commonly used in the art, as long as the purpose of the present invention is not impaired. good.

Various anorexia-improving compositions of the present invention may be administered by any route, for example, oral administration, intravenous administration, intrarectal administration, or the like. The form of the composition can be arbitrarily selected depending on the route of administration, for example, solid forms such as tablets, granules, powders, and capsules, or solid forms such as solutions, suspensions, and emulsions. It may be a liquid agent, or various beverages or foods. Further, the composition can be manufactured by any method commonly used in the art.

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the scope of the present invention is not limited to these Examples.

[Example 1]
Young (2.5 months old) or old (10 months old) male ICR mice were fed powdered feed (CE-2, CLEA Japan) in individual cages lined with ALPHA-dri (Shepherd Specialty Papers). The mice were acclimatized for at least one week while being fed using a powder feeder for mice (SN-950, Shinano Seisakusho Co., Ltd.). Then, for several days before the experiment, oral administration training using a handling and feeding needle (FG4202, Fuchigami Kikai Co., Ltd.) was performed every day.

Ghrelin (4373-s, Peptide Institute Co., Ltd.) physiological saline solution or physiological saline was administered intraperitoneally (5 mL/kg body weight) to mice under ad libitum feeding conditions from 9:20 a.m., or DATS solution (2% DATS/ethanol, 10% Tween 80, and 88% saline) or carrier solution was administered orally (5 mL/kg body weight). The dose of ghrelin was 30 nmol/kg body weight, and the dose of DATS was 100 μmol/kg body weight. Then, at 9:30 a.m., a feeder whose mass had been measured in advance was set in the cage. The mass of the food spilled into the feeder and cage 0.5, 1, 2, 3, and 24 hours after the start of the feeding experiment was measured, and the mass of food eaten (g) at each time was measured. The intake amount (kcal) was calculated from the energy value of CE-2, 3.45 kcal/g. The results are shown in Figures 1-4.

Comparing the average daily food intake (energy intake) per body weight, young mice ingested 507 kcal/kg of body weight, while older mice only ingested 342 kcal/kg of body weight. It was found that appetite decreases with age. Food intake in young mice was enhanced by ghrelin (Figure 1) and also by DATS (Figure 2). On the other hand, the food intake of aged mice was not enhanced by ghrelin (Figure 3), but was enhanced by DATS (Figure 4). Therefore, it was found that aged mice have become ghrelin resistant, and the decreased appetite of aged mice cannot be improved by ghrelin, and that the anorexia of aged mice that are ghrelin resistant can be improved by DATS.

[Example 2]
A 9-week-old male ICR mouse was restrained for 2 hours in a restraint device made of a 100 mL tube to give stress. During the corresponding 2 hours, the control unrestrained stress group was allowed to fast only. Thereafter, the DATS solution or carrier solution was orally administered (5 mL/kg body weight) to each mouse, and the amount of food intake was measured over time. The dose of DATS was 100 μmol/kg body weight, and the test groups of groups 1 to 4 were as shown in the table below. The results are shown in FIG.

Compared to mice without restraint stress (group 1) that were administered with the carrier solution, cumulative food intake was lower in mice with restraint stress (group 3), indicating that stress-induced anorexia was formed due to restraint stress loading. It was confirmed that there is. In this test system, when DATS was administered, food intake was increased not only in mice without restraint stress (group 2) but also in mice with restraint stress (group 4). As a result, the food intake of mice with restraint stress (group 4) recovered to the food intake of mice without restraint stress (group 1). Therefore, it was found that stress-induced anorexia can be improved by DATS. The anorexia-improving effect of DATS lasted for at least 3 hours after administration.

From the above, TRPA1 agonists such as DATS can improve anorexia in elderly people, anorexia in ghrelin-resistant subjects, and/or stress-induced anorexia.

Claims (5)

A composition for improving anorexia in elderly people, comprising a transient receptor potential ankyrin 1 (TRPA1) agonist,
The composition, wherein the TRPA1 agonist is diallyl trisulfide. 2. The composition of claim 1, wherein the elderly is ghrelin resistant. A composition for improving anorexia in a ghrelin-resistant subject, comprising a TRPA1 agonist,
The composition, wherein the TRPA1 agonist is diallyl trisulfide. A composition for improving stress-induced anorexia, comprising a TRPA1 agonist,
The composition, wherein the TRPA1 agonist is diallyl trisulfide. The composition according to any one of claims 1 to 4, which is a pharmaceutical, a quasi-drug, a supplement, or a food.

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